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Method of treating conditiions with kinase inhibitors

a kinase inhibitor and conditiion technology, applied in the field of methods, can solve the problems of malignant tumor growth, abnormal blood vessel growth, malignant tumor growth, etc., and achieve the effect of increasing the hydrophilicity of the molecule and increasing the solubility of the otherwise hydrophobic compound

Active Publication Date: 2013-09-12
ALLERGAN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention relates to a method for increasing the solubility of a molecule by adding a polar radical to one of its components. This makes the molecule more likely to dissolve in water and other liquids. The location of the added polar radical is important, as it helps to increase the hydrophilicity (ability to dissolve in water) of the molecule. This can be useful for improving the performance of the molecule in some applications.

Problems solved by technology

Aberrant expression or mutations in the PTKs have been shown to lead to either uncontrolled cell proliferation (e.g. malignant tumor growth) or to defects in key developmental processes.
In ophthalmic diseases such as neovascular age-related macular degeneration and diabetic retinopathy aberrant activation of VEGF receptors can lead to abnormal blood vessel growth.

Method used

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  • Method of treating conditiions with kinase inhibitors
  • Method of treating conditiions with kinase inhibitors
  • Method of treating conditiions with kinase inhibitors

Examples

Experimental program
Comparison scheme
Effect test

preparation 1

[0105]

Methyl-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoate

[0106]Procedure adopted from Tetrahedron Lett., 2007, 48, 2519. A thick-walled glass reaction vessel was charged with palladium(II)acetate (235 mg, 1.05 mmol), X-Phos (500 mg, 1.05 mmol, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), cesium carbonate (6.82 g, 20.95 mmol) and 5:1 (v / v) toluene:t-BuOH (20 mL). The stirred contents were purged with nitrogen and a solution of 4-piperidone ethylene ketal (2.70 mL, 20.95 mmol) and methyl-3-bromobenzoate (4.95 g, 23.02 mmol) in 5:1 (v / v) toluene:t-BuOH (100 mL) was added. After stirring for 2 minutes, the vessel was sealed and the reaction mixture was heated at 120° C. for 16 hours. Upon cooling to room temperature, the reaction mixture was filtered through celite and the filtrate was concentrated.

[0107]Elution through a flash column (silica gel 60, 230-400 mesh, 7:3 hexanes:EtOAc) followed by concentration gave the title compound as an oil (5.64 g, 97%).

preparation 2

[0108]

Methyl-3-(4-oxopiperidin-1-yl)-benzoate

Method A:

[0109]A solution of methyl-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoate (3.85 g, 13.88 mmol) in 10% aqueous sulfuric acid (40 mL and THF (40 mL) was stirred at ambient temperature for 14 days. The reaction mixture was neutralized by cautious addition of NaHCO3 and simultaneously diluting with water. The aqueous mixture was extracted with EtOAc (2×75 mL) and the combined organic extracts were dried (MgSO4), filtered, and concentrated to give the title compound as an oil (2.75 g, 85%) which was used without further purification.

Method B:

[0110]A mixture of methyl-3-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-benzoate (1.80 g, 6.49 mmol) and p-toluenesulfonic acid monohydrate (123 mg, 0.649 mmol) in water (30 mL) and acetone (15 mL) was heated at reflux for 17 hours. The organic solvent was removed in vacuo and the aqueous mixture was extracted with dichloromethane. The organic extract was washed with saturated NaHCO3(aq.), dried (MgSO4), ...

preparation 3

[0111]

Methyl-3-(3-dimethylaminomethylene-4-oxopiperidin-1-yl)-benzoate

[0112]A solution of methyl-3-(4-oxopiperidin-1-yl)-benzoate (2.72 g, 11.66 mmol) and DMF-dimethylacetal (6.24 mL, 46.64 mmol) in 1,4-dioxane (50 mL) was refluxed for 43 hours. The reaction mixture was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 5% MeOH in EtOAc to 8% MeOH in EtOAc) to obtain the title compound as a red oil which slowly crystallized on standing (1.52 g, 45%).

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Abstract

The present invention relates to a method of treating ophthalmic diseases and conditions, e.g. diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, etc., in a subject comprising administering to said subject a therapeutically effective amount of at least one compound of formula Ior a prodrug, pharmaceutically acceptable salt, racemic mixtures or enantiomers of said compound. The compounds of formula I are capable of modulating tyrosine kinase signal transduction in order to regulate, modulate and / or inhibit abnormal cell proliferation.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application Ser. No. 61 / 609,742, filed on Mar. 12, 2012, all of which is incorporated herein by reference herein in its entirety.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention is directed to methods of regulating, modulating or inhibiting tyrosine kinases, whether of the receptor or non-receptor class, for the prevention and / or treatment of disorders related to unregulated tyrosine kinase signal transduction, including cell growth, metabolic disorders and blood vessel proliferative disorders.[0004]2. Description of the Related Art[0005]Protein tyrosine kinases (PTKs) comprise a large and diverse class of proteins having enzymatic activity. The PTKs play an important role in the control of cell growth and differentiation. For example, receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific g...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D471/04C07D487/04
CPCC07D471/04C07D487/04A61K31/437A61K31/4375A61K31/519A61K31/5377A61P27/02
Inventor HULL, III, CLARENCE E.MALONE, THOMAS C.
Owner ALLERGAN INC
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